Exploration of Natural Products for Targeting IDH1 and IDH2 Mutations in Acute Myeloid Leukemia Through Ligand-Based Pharmacophore Screening and Molecular Dynamic Simulation Approaches

Background Mutations in isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are prevalent drivers of acute myeloid leukemia (AML). While targeted therapies exist, resistance can emerge. This study explored the potential of natural products to identify novel dual IDH inhibitors. Methods In-silico screening of the COCONUT database was performed using Lipinski’s Rule of Five. Pharmacophore modelling identified crucial features for IDH binding. Docking simulations with Glide (Schrödinger) assessed binding affinity, followed by MM-GBSA calculations for free energy estimation. The most promising candidate underwent ADME/T and toxicity analysis. Finally, molecular dynamics (MD) simulations evaluated the stability of protein-ligand complexes and binding interactions, followed by trajectory analysis using DCCM and PCA. Results The study identified Ternstroside D (CNP0166496) as a potential dual inhibitor for IDH1 and IDH2 mutations. Docking simulations and MM-GBSA calculations predicted favourable binding affinities. MD simulations revealed stable protein-ligand complexes, and in-silico ADME/T analysis suggested good drug-like properties and a favorable safety profile for CNP0166496. Conclusion This in-silico study provides compelling evidence for Ternstroside D (CNP0166496) as a promising dual inhibitor for IDH1 and IDH2 mutations in AML. Further in-vitro and in-vivo studies are warranted to validate these findings.